Osteosarcoma - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main osteosarcoma page for current regimens.

8 regimens on this page 8 variants on this page

Neoadjuvant therapy

MA-BCD

MA-BCD: High-dose Methotrexate, Adriamycin (Doxorubicin), Bleomycin, Cyclophosphamide, Dactinomycin

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winkler et al. 1984 (COSS-80)	1979-1982	Phase 3 (C)	MAP	Did not meet primary endpoint of CDF rate

Note: The exact schedule is unclear based on limited/conflicting information in the reference. For example, Figure 1 appears to depict high-dose methotrexate starting 2 weeks after adriamycin, but the text says that methotrexate begins after a 3-week rest period. Additionally, the diagram in Figure 1 implies that the later therapies are given 4 times (once, then repeated x 3 cycles), but based on the cumulative doses listed, they are only given for a total of 3 cycles. The optional interferon arm is omitted given lack of benefit seen in the study.

Chemotherapy, part 1

• Doxorubicin (Adriamycin) 45 mg/m² IV bolus once per day on days 1 & 2

21-day course, then

Chemotherapy, part 2

See note above about uncertainty about the exact schedule.

• Methotrexate (MTX) 12,000 mg/m² (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1 & 8
  • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
• Bleomycin (Blenoxane) 12 mg/m² IV bolus once per day on days 15 & 16
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once per day on days 15 & 16
• Dactinomycin (Cosmegen) 0.45 mg/m² IV bolus once per day on days 15 & 16

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² PO every 6 hours x 12 hours once per day on days 2 & 9, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
• Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
• NS 4.5 L/m² on day 1 after methotrexate; NS 3 L/m² on day 2, with adjustments made to keep urine pH greater than 7.4

35-day course, followed by:

Chemotherapy, part 3

See note above about uncertainty about the exact schedule.

• Methotrexate (MTX) 12,000 mg/m² (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1, 8, 29, 36
  • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
• Doxorubicin (Adriamycin) 45 mg/m² IV bolus once per day on days 15 & 16 (delayed during cycle 1 until after surgery)
• Bleomycin (Blenoxane) 12 mg/m² IV bolus once per day on days 43 & 44
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once per day on days 43 & 44
• Dactinomycin (Cosmegen) 0.45 mg/m² IV bolus once per day on days 43 & 44

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² PO every 6 hours x 12 hours once per day on days 2, 9, 30, 37, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
• Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
• NS 4.5 L/m² on day 1 after methotrexate; NS 3 L/m² on day 2, with adjustments made to keep urine pH greater than 7.4

8-week cycle for 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9 to 18 weeks after the start of chemotherapy

References

1. COSS-80: Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U, Havers W, Henze G, Hinderfeld L, Höcker P, Jobke A, Jürgens H, Kabisch H, Preusser P, Prindull G, Ramach W, Ritter J, Sekera J, Treuner J, Wist G, Landbeck G. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984 Jun;2(6):617-24. link to original article contains dosing details in manuscript PubMed

M-BCD

M-BCD: High-dose Methotrexate, Bleomycin, Cyclophosphamide, Dactinomycin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Winkler et al. 1988 (COSS-82)	1982-1984	Phase 3 (C)	MAP	Inferior ORR

Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time.

Chemotherapy

• Methotrexate (MTX) 12,000 mg/m² (maximum dose of 20,000 mg) IV over 4 hours once per day on days 15 & 22
  • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
• Bleomycin (Blenoxane) 15 mg/m² IV bolus once per day on days 1 & 2
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once per day on days 1 & 2
• Dactinomycin (Cosmegen) 0.6 mg/m² IV bolus once per day on days 1 & 2

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² PO every 6 hours x 12 hours once per day on days 16 & 23, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
• Sodium bicarbonate urine alkalinization prior to high-dose Methotrexate (MTX)
• NS 4.5 L/m² on day 1 after Methotrexate (MTX); NS 3 L/m² on day 2, with adjustments made to keep urine pH greater than 7.4

35-day cycle for 2 cycles

Subsequent treatment

• Surgery, then risk-adapted treatment:
  • Patients who had a good response: Adjuvant M-BCD
  • Patients who had a poor response: Adjuvant AP

References

1. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed

Adjuvant therapy

Doxorubicin monotherapy

Regimen

Study	Evidence
Cortes et al. 1974	Non-randomized

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 to 3

4- to 6-week cycle for 6 cycles

References

1. Cortes EP, Holland JF, Wang JJ, Sinks LF, Blom J, Senn H, Bank A, Glidewell O. Amputation and adriamycin in primary osteosarcoma. N Engl J Med. 1974 Nov 7;291(19):998-1000. link to original article contains dosing details in abstract PubMed

IP-BCD

IP-BCD: Ifosfamide, Platinol (Cisplatin), Bleomycin, Cyclophosphamide, Dactinomycin

Regimen

Study	Years of enrollment	Evidence
Winkler et al. 1988 (COSS-82)	1982-1984	Non-randomized portion of phase 3 RCT

Preceding treatment

• Neoadjuvant MAP, then surgery, with poor response

Chemotherapy

• Ifosfamide (Ifex) 2000 mg/m² IV over 23.5 hours once per day on days 1 to 5, given second, with mesna
• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 to 5, given first
• Bleomycin (Blenoxane) 15 mg/m² IV bolus once per day on days 22 & 23
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once per day on days 22 & 23
• Dactinomycin (Cosmegen) 0.6 mg/m² IV bolus once per day on days 22 & 23

Supportive therapy

• Mesna (Mesnex) 2000 mg/m² IV over 23.5 hours once per day on days 1 to 5, given second, with Ifosfamide (Ifex), then 2000 mg/m²/day IV continuous infusion over 48 hours, started on day 6 (total dose: 14,000 mg/m²)
• Mannitol given with Cisplatin (Platinol); no further details provided

35-day cycle for 3 cycles

References

1. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed

MA-BCD/AP

MA-BCD/AP: High-dose Methotrexate, Adriamycin (Doxorubicin), Bleomycin, Cyclophosphamide, Dactinomycin alternating with Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Link et al. 1986	1982-1984	Phase 3 (E-esc)	No further treatment	Superior RFS

Preceding treatment

• Surgery

Chemotherapy

• Methotrexate (MTX)
• Doxorubicin (Adriamycin)
• Bleomycin (Blenoxane)
• Cyclophosphamide (Cytoxan)
• Dactinomycin (Cosmegen)
• Doxorubicin (Adriamycin)
• Cisplatin (Platinol)

References

1. Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, Ayala AG, Shuster JJ, Abelson HT, Simone JV, Vietti TJ. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986 Jun 19;314(25):1600-6. link to original article PubMed

M-BCD

M-BCD: High-dose Methotrexate, Bleomycin, Cyclophosphamide, Dactinomycin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Eilber et al. 1987	1981-1984	Randomized (E-esc)	Observation	Seems to have superior OS
Winkler et al. 1988 (COSS-82)	1982-1984	Non-randomized portion of phase 3 RCT

Note: The exact schedule is unclear based on limited information in the references; schedule of doses is primarily extrapolated from Figure 1 of Winkler et al. 1988, which does not contain clear delineations in time.

Preceding treatment

• Neoadjuvant M-BCD, then surgery, with good response

Chemotherapy

• Methotrexate (MTX) 12,000 mg/m² (maximum dose of 20,000 mg) IV over 4 hours once per day on days 15 & 22
  • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
• Bleomycin (Blenoxane) 15 mg/m² IV bolus once per day on days 1 & 2
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once per day on days 1 & 2
• Dactinomycin (Cosmegen) 0.6 mg/m² IV bolus once per day on days 1 & 2

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² PO every 6 hours x 12 hours once per day on days 16 & 23, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
• Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
• NS 4.5 L/m² on day 1 after methotrexate; NS 3 L/m² on day 2, with adjustments made to keep urine pH greater than 7.4

35-day cycle for 2 cycles

References

1. Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol. 1987 Jan;5(1):21-6. link to original article PubMed
   1. Update: Bernthal NM, Federman N, Eilber FR, Nelson SD, Eckardt JJ, Eilber FC, Tap WD. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer. 2012 Dec 1;118(23):5888-93. Epub 2012 May 30. link to original article PubMed
2. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed

Methotrexate & Vincristine

Regimen

Study	Evidence
Jaffe et al. 1974	Non-randomized

Preceding treatment

• Surgery

Chemotherapy

• Methotrexate (MTX)
• Vincristine (Oncovin)

Supportive therapy

• Folinic acid (Leucovorin)

21-day cycle for up to 35 cycles (2 years)

References

1. Jaffe N, Frei E 3rd, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med. 1974 Nov 7;291(19):994-7. link to original article PubMed

Relapsed, refractory, or metastatic

Doxorubicin monotherapy

Regimen

Study	Evidence
Cortes et al. 1972	Non-randomized, <20 pts

Chemotherapy

• Doxorubicin (Adriamycin)

References

1. Cortes EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA. 1972 Sep 4;221(10):1132-8. link to original article PubMed

MAPifn [COG AOST0331]

Note: Induction is received by all patients and consists of 2 cycles of MAP. The remainder of this protocol is for good responders.

Induction

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV infusion over 4 hours, started on day 1 of weeks 1 and 6
• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Weeks 1 and 6
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 4, 5, 9, and 10.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

10 Week course

Consolidation, Cycles 3-4

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV infusion over 4 hours, started on day 1 of weeks 12 and 17
• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Weeks 12 and 17.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 15, 16, 20, and 21.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

10 Week course

Consolidation, Cycles 5-6

Chemotherapy

• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Weeks 22 and 26.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 24, 25, 28, and 29.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

10 Week course

Maintenance, Weeks 30-104

Chemotherapy

• Peginterferon alfa-2b (PegIntron) 0.5 mcg/kg/day (MAX DOSE = 50 mcg) subcutaneously on day 1 of Weeks 30, 31, 32, and 33.
  • If well tolerated during first 4 weeks of therapy, escalate dose.
• Peginterferon alfa-2b (PegIntron) 1 mcg/kg/day (MAX DOSE = 100 mcg) subcutaneously on day 1 of Weeks 34 through 104.

75 Week course

References

1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00134030

MAPIE [COG AOST0331]

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Marina et al. 2016 (EURAMOS-1 poor response)	2005-2011	Phase 3 (E-esc)	MAP	Did not meet primary endpoint of EFS

Note: Induction is received by all patients and consists of 2 cycles of MAP; subsequent treatments in this protocol are for poor responders.

Induction

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV infusion over 4 hours, started on day 1 of weeks 1 and 6
• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Weeks 1 and 6
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 4, 5, 9, and 10.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

10 Week course

Consolidation, MAPIE Cycles 3 and 7

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV infusion over 4 hours, started on day 1 of weeks 12 and 28
• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Weeks 12 and 28.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 15 and 31.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

5-Week Courses

Consolidation, MAP Cycles 4, 6, and 8

Chemotherapy

• Ifosfamide (Ifex) 2.8 g/m²/dose IV over 4 hours once per day on days 1 through 5 of weeks 16, 24, and 32.
• Etoposide (Vepesid) 100 mg/m²/dose IV over 60 minutes once per day on days 1 through 5 of weeks 16, 24, and 32.
• Mesna (Mesnex) 2.8 g/m²/24 hours IV continuous infusion over 24 hours on days 1 through 5 of weeks 16, 24, and 32.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 19, 27, and 35.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

5-Week Courses

Consolidation, MAP Cycle 5

Chemotherapy

• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Week 20.
• Ifosfamide (Ifex) 3 g/m²/dose IV over 4 hours once per day on days 1, 2, and 3 of weeks 20.
• Mesna (Mesnex) 3 g/m²/24 hours IV continuous infusion over 24 hours on days 1, 2, and 3 of weeks 20.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 23.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

5-Week Courses

Consolidation, MAP Cycle 9

Chemotherapy

• Doxorubicin (Adriamycin) 37.5 mg/m²/day (total dose is 75 mg/m² given as a 48 hour infusion) on days 1 to 2 of Week 36.
• Ifosfamide (Ifex) 3 g/m²/dose IV over 4 hours once per day on days 1, 2, and 3 of weeks 36.
• Mesna (Mesnex) 3 g/m²/24 hours IV continuous infusion over 24 hours on days 1, 2, and 3 of weeks 36.
• Methotrexate (MTX) 12 g/m² (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 39 and 40.
• Folinic acid (Leucovorin) 15 mg/m² PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

5-Week Courses

References

1. EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00134030